Differential Role of B Cells and IL-17 Versus IFN-γ During Early and Late Rejection of Pig Islet Xenografts in Mice. Issue 8 (August 2017)

• Record Type: Journal Article
• Authors: Kang, Hee Kap; Wang, Shusen; Dangi, Anil; Zhang, Xiaomin; Singh, Amar; Zhang, Lei; Rosati, James M.; Suarez-Pinzon, Wilma; Deng, Xuelian; Chen, Xiaoyan; Thorp, Edward B.; Hering, Bernhard J.; Miller, Stephen D.; Luo, Xunrong
• Is Part Of: Transplantation. Volume 101:Issue 8(2017)
• Publication Date: 2017-08
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001489
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Xenogeneic islet transplantation is an emerging therapeutic option for diabetic patients. However, immunological tolerance to xenogeneic islets remains a challenge. Methods: The current study used a pig-to-mouse discordant xenogeneic islet transplant model to examine antidonor xenogeneic immune responses during early and late rejection and to determine experimental therapeutic interventions that promote durable pig islet xenograft survival. Results: We found that during early acute rejection of pig islet xenografts, the rejecting hosts exhibited a heavy graft infiltration with B220 + B cells and a robust antipig antibody production. In addition, early donor-stimulated IL-17 production, but not IFN-γ production, dominated during early acute rejection. Recipient treatment with donor apoptotic 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide-treated splenocytes significantly inhibited antidonor IL-17 response, and when combined with B cell depletion and a short course of rapamycin led to survival of pig islet xenografts beyond 100 days in approximately 65% recipients. Interestingly, treated recipients in this model experienced late rejection between 100 and 200 days posttransplant, which coincided with B cell reconstitution and an ensuing emergence of a robust antidonor IFN-γ, but not IL-17, response. Conclusions: These findings reveal that early and late rejection of pig islet xenografts may be dominated by different immune responses and that maintenance of long-term xenogeneic tolerance will require strategies that target the temporal sequence of antixenogeneic immune responses. Abstract : The authors investigate the anti-donor xenogeneic immune responses in a pig-to-mouse islet transplant model. It has been demonstrated that B cells play differential roles in early and late rejection by producing IL17 or IFN-γ, respectively. Supplemental digital content is available in the text.